This program project grant will determine the imaging, emotional, social-cognitive, language, genetic and diagnostic features of frontotemporal lobar degeneration (FTLD) and related disorders including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP) and amyotrophic lateral sclerosis (ALS) in contrast to Alzheimer's disease (AD) and healthy aging. In project 2 we will explore the imaging features of the three major FTLD syndromes and a new cohort of patients with ALS using a 4.0 Tesla magnet. This project will use new imaging techniques including tensor-based morphometry, perfusion and diffusion tensor imaging. In project three we will use methods derived from basic emotion research to evaluate emotional functioning (reactivity, regulation, knowledge) in all three FTLD subtypes compared to AD. Dyads interaction between patients and caregivers, low-level emotion processing and higher order reactions to these basic emotional stimulations will be determined. Project 4 will use all of the information captured through the clinical core, genetics core as well as new amyloid imaging and proteomics parameters to explore better separation of FTLD subtypes from each other and from AD, early diagnosis and better prediction of patients with FTLD-associated tau pathology from those with FTLD-ubiquitin pathology. A new project 5 explores brain-behavior relationships in FTLD using novel and innovative cognitive and social probes. Using 4.0 Tesla scans from project 2 the relationship between changes in the dorsal frontal regions and specific aspects of cognitive control of motor responses and regulation of emotion, the relationship between changes in the ventral and medial prefrontal regions and activation of the emotional systems for monitoring of behavior and the relationship between the anterior temporal lobe and comprehension of verbal and non-verbal stimuli will be explored. Project 1 which was focused upon finding novel genes associated with FTLD is replaced by a Genetics Core that will not only perform routine studies of apolipoprotein E, tau, and presenilin 1, but will also explore mRNA expression of tau-related and frontal lobe related genes. Through the Clincial Core novel assessment of 107 AD, 131 FTD, 67 SD, 56 PNFA, 43 CBD, 30 PSP, 59 ALS, and 89 controls will be completed by year 10. Neuropathology will be completed in 37 AD, 64 FTD, 25 SD, 23 PNFA, 23 CBD, 23 PSP and 27 ALS patients. This PPG represents one of the largest efforts to understand the clinical features of FTLD ever performed. PRINCIPAL INVESTIGATOR: Dr. Miller received his medical and neurologic training at the University of British Columbia. He then completed a post-doctoral fellowship in Behavioral Neurology at the University of California, Los Angeles (UCLA). His interest in Frontotemporal Lobar Degeneration (FTLD) began when he was at UCLA and it continues to be his primary interest. There are few research groups in the world that focus on FTLD, perhaps because it has been so difficult to reconcile its'heterogeneous clinical and neuropathologic presentation. Dr. Miller has assembled an interdisciplinary team of investigators with expertise in the clinical, behavioral, neuropathological, imaging and genetic issues related to FTLD. It is clearly one of the premier groups in the world working in this area. FTLD is an understudied, important and particularly challenging, area of investigation. Taken as a whole, this program project represents one of the best groups in the world attempting to understand and treat this patient population. REVIEW OF THE COMPONENTS CORE A - CLINICAL AND ADMINISTRATIVE;DR. BRUCE L. MILLER DESCRIPTION (provided by applicant): The Clinical and Administrative Core provides essential operational functions for the entire PPG. This Core will recruit patients with frontotemporal dementia (FTD), semantic dementia (SD), progressive non-fluent aphasia (PNFA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and normal control subjects. Each subject will receive a comprehensive evaluation measuring a broad range of neurological, neuropsychological, functional, neurobehavioral, and social-personality variables. In addition, subjects will be followed annually to collect longitudinal data and maintain high enrollment in our autopsy program. Administrative functions of this Core include the infrastructure for establishing policies and procedures, maintaining communication within the PPG and between the PPG and the scientific community, ensuring optimal utilization and monitoring of PPG resources, and ensuring the scientific and ethical integrity of all PPG practices. Once recruited into the Clinical and Administrative Core, subjects will be referred to Projects 2 (Imaging;Dr. Weiner), 3 (Emotion;Dr. Levenson), 4 (Clinical Diagnosis;Dr. Miller), and 5 (Brain-Behavior;Dr. Rosen). In addition, blood samples will be sent to the Genetics Core (Dr. Geschwind) and autopsy tissue will be sent to the Pathology Core (Drs. Trojanowski and Lee). The Clinical and Administrative Core will also interact extensively with the Data Management and Biostatistics Core (Dr. Fox) for data management, data quality, and data analysis functions.